PRIDE-HD
(2020)Objective
To evaluate whether pridopidine, a sigma-1 receptor agonist, improves or stabilizes functional capacity in early-stage Huntington's disease (HD) as measured by the Total Functional Capacity (TFC) scale.
Study Summary
• Higher percentage of patients in pridopidine group had stable or improved TFC at 52 weeks
• Benefit observed across multiple functional domains: ADLs, domestic chores, finances, and care level
Intervention
Randomized, placebo-controlled, phase 2 trial extended to 52 weeks. Patients with HD were assigned to various doses of pridopidine or placebo. Post-hoc analysis focused on 45 mg BID dose vs placebo, particularly in early-stage HD (TFC 7–13). Primary endpoint was change in TFC.
Inclusion Criteria
• Confirmed diagnosis of Huntington's disease
• TFC score between 7 and 13 (early-stage HD)
• Ability to provide informed consent
• Completion of at least one dose and post-baseline assessment
Study Design
Arms: Placebo, Pridopidine 45 mg BID
Patients per Arm: Placebo: 62, Pridopidine: 59 (early HD subgroup)
Outcome
• Fewer non-responders (TFC decline) in pridopidine group: 18.9% vs 51.2%, OR 0.20 (95% CI: 0.07–0.56, p=0.002)
• cUHDRS also improved (mean difference +0.6, p=0.04)
Bottom Line
Pridopidine did not improve UHDRS Total Motor Score in HD: -0.7 (45mg BID) vs -0.2 (placebo); P=0.32. Phase 2, 52-week, dose-finding. Published JAMA Neurol 2019. 408 patients, 4 dose groups. Sigma-1 receptor agonist mechanism explored post-hoc.
Major Points
- Primary endpoint not met: UHDRS-TMS change -0.7 (45mg BID) vs -0.2 (placebo); P=0.32.
- No dose group (22.5, 45, 67.5, or 112.5 mg BID) significantly improved TMS.
- 408 HD patients. 52-week, double-blind, placebo-controlled, dose-finding (Phase 2).
- Secondary endpoints also negative: TFC, UHDRS-IS, CGI-C all non-significant.
- Post-hoc: possible signal in TFC preservation at 45mg dose — explored in PROOF-HD (Phase 3, failed).
- Pridopidine: initially developed as dopamine stabilizer, reclassified as sigma-1 receptor agonist.
- Well tolerated: AEs similar across groups. Falls, nausea, diarrhea most common.
- Teva Pharmaceutical sponsored. Published JAMA Neurol 2019 (Reilmann et al.).
- Sigma-1 mechanism may target neuroprotection rather than symptomatic motor improvement.
- PROOF-HD (Phase 3, n=499) also failed primary endpoint — pridopidine development halted for HD.
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled, phase 2 trial with post hoc subgroup analysis
- Randomization
- Yes
- Blinding
- Double-blind (patients and investigators)
- Sample Size
- 408
- Follow-up
- 52 weeks
- Centers
- 57
- Countries
- USA, Canada, Europe, Australia
Primary Outcome
Definition: Change in Total Functional Capacity (TFC) score from baseline to 52 weeks
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| Greater decline in placebo group | Mean difference +1.16 vs placebo | - (Not provided) | 0.0003 |
Limitations & Criticisms
- Primary analysis was post hoc and not pre-specified
- Study not powered for clinical outcomes in early HD subgroup
- No imaging or biomarker data to support disease-modifying claims
- Functional scales may be prone to subjective interpretation
Citation
Neurology. 2020;95(6):e805-e814. doi:10.1212/WNL.0000000000009823